A number of lines of evidence strongly suggest that the disposition kinetics of digoxin are determined largely by the activity of the MDR1 gene product, the P-glycoprotein efflux pump. Recent studies in human subjects indicate that expression of MDR1 can vary 50-fold among individuals and in animal models is induced to a variable extent by exposure to environmental carcinogens such as those contained in tobacco smoke. The overall objective of this study, therefore, is to determine the distribution of P-glycoprotein-dependent efflux mechanisms in the disposition of digoxin in a population of human subjects (smokers and nonsmokers). Increasing the number of subjects to complete the study is our immediate concern.